#ASCO12 Data Digest: Combating Resistance in Lung Cancer

The American Society of Clinical Oncology (ASCO) meeting, held in Chicago earlier this month, brought some fascinating presentations on progress in two very tough to treat cancer types, lung cancer and advanced melanoma. This week, we’ll take a look at some of the data that emerged out of ASCO on small molecules that could overcome the limitations of existing therapies.

Treatment for lung cancer and melanoma has commonalities. Small molecule kinase inhibitors targeting a particular aberration driving the tumor have been approved for both types of cancer. But in each case, tumors eventually develop resistance to those kinase inhibitors, usually after about 6 to 9 months of treatment. Researchers are now trying to pinpoint the mechanism that tumor cells use to overcome the activity of kinase inhibitors, and then design new compounds or combinations of drugs that can improve patient outcomes.

First, some background on the current treatment paradigm in NSCLC: To date, scientists have identified several key protein receptors—EGFR, KRAS, and ALK—as drivers of the disease. Patients with a mutation in EGFR can take Genentech’s Tarceva (erlotinib) or AstraZeneca’s Iressa (gefitinib), but only after undergoing four cycles of chemotherapy. Although Tarceva was approved based on its ability to shrink tumors, it only prolongs survival in NSCLC patients by one month (12 months Tarceva vs. 11 months for placebo). Meanwhile, people who have the anaplastic lymphoma kinase (ALK-ELM4) translocation, can receive Pfizer’s Xalkori (crizotinib), which was approved in the U.S. in 2011.

Unfortunately, people with the KRAS mutation, which is considered mutually exclusive with EGFR, do not benefit from either additional chemotherapy or EGFR inhibitors. New therapies are desperately needed, since prognosis tends to be rather poor.

At ASCO this year, clinicians reported new data that answered some key questions about how best to treat people with these particular mutations:

Does a pan-ErbB inhibitor produce better results upfront than chemotherapy?

Unlike Tarceva and Iressa, which target only EGFR (also known as ErbB1), Boehringer Ingelheim’s drug candidate afatinib is a pan-Erb inhibitor that targets ErbB1, B2 and B4. The idea behind afatinib is to determine whether an irreversible pan Erb inhibitor with preclinical activity against the T790M mutation, which is known to induce resistance to erlotinib, would be more effective.

In this phase III randomized trial, patients with the EGFR mutation were randomized 2:1 to receive either afatinib (40 mg/day) or cisplatin plus pemetrexed for up to 6 cycles. The primary endpoint was progression free survival (PFS), with response rate and OS among the secondary endpoints.

The results were very encouraging – not only did afatinib demonstrate solid PFS versus chemotherapy (11.1 vs 6.9 months, HR 0.58, P=0.0004), but it also showed activity in common mutations such as Del19 and L858R (13.6 vs. 6.9 months), which are known to cause resistance to Tarceva. Overall survival data were not yet available.

Based on these impressive data and the attainment of the primary endpoint (PFS), the trial was unblinded, which means that determining OS may well be compromised. These results suggest a preferential role for afatinib over standard chemotherapy in treating patients with mutant EGFR in the first line setting. Boehringer will likely seek U.S. and European regulatory approval in newly diagnosed EGFR mutant NSCLC based on the Phase III trial in the near future.

What new advances are there for patients with KRAS mutations?

Outside of Asia, KRAS is the most frequently mutated oncogene in NSCLC, affecting roughly 20% of the patient population. But to date, there are no targeted therapies approved for this subset. Worse, patients with the KRAS mutation generally don’t respond as well to chemotherapy as those without KRAS mutations.

One trial at ASCO that caught my eye looked at the role of a MEK inhibitor, AstraZeneca’s selumetinib (AZD6244) in KRAS mutant NSCLC. The phase II study compared the effect of selumetinib (75 mg BID) plus docetaxel (75 mg/m2) with placebo and docetaxel in second line disease. The response rates in the selumetinib arm were impressive, showing a 26% greater reduction in tumor size than the control arm (P=0.004). PFS was significantly improved (5.3 vs 2.1 months, P=0.01), while OS was affected by crossover of the arms at around 350 days (9.4 vs 5.2 months, P=0.207). My takeaway is that selumetinib warrants further research in KRAS-mutant NSCLC, with perhaps a look at dosing and scheduling changes to see if they affect the outcomes.

Another trial looked at the potential role of Eli Lilly’s Alimta with and without its EGFR-targeted monoclonal antibody Erbitux, in NSCLC patients with KRAS mutations. Based on a promising phase II study with an objective response rate of 28%, the presenter Ed Kim (MD Anderson) noted that there was sufficient rationale to pursue a phase III randomized trial. Unfortunately, this large-scale randomized trial was futile – patients on chemotherapy alone did better than those on the combination! Until we have a biomarker of response for Erbitux, this drug (approved for colon and head & neck cancers) is unlikely to see much action in lung cancer.

How do we overcome ALK resistance?

Pfizer’s Xalkori, approved last year to treat the small percentage of the NSCLC population, works very well—for awhile. Eventually, resistance sets in and researchers are trying to figure out how to address the issue.

There are several logical ways of looking at this challenge. One is to find a more potent and selective inhibitor; the other is to identify the mechanisms of acquired resistance to Xalkori and then consider new rational approaches, either in combination or in sequence.

Robert Doebele (University of Colorado) provided an in-depth overview of mechanisms of resistance to ALK kinase inhibitors in ALK+ NSCLC. Essentially, while most patients respond initially to Xalkori, acquired resistance develops in several ways.

The most common element of resistance was the development of ALK mutations (31%), which is entirely expected with what we now from treatment with kinase inhibitors in general.

Previously, however, ALK translocations and EGFR mutations were considered to be mutually exclusive, but the presence of EGFR mutations (12%) in the development of acquired resistance to crizotinib may suggest either a role for combining them or a dual inhibitor of both targets might be potentially useful strategy to consider. The emergence of KRAS mutations (19%) is very consistent with what we know about NSCLC.

Though early in clinical development, a promising new ALK inhibitor, Novartis’ LDK378, emerged at this ASCO. Preclinical studies suggested the compound is more potent and selective than Xalkori. At ASCO, the results from the first trial in humans reinforced the enzymatic and cell-based tests. The primary goal of the Phase I study (led by Mehra et al) was to establish the maximum tolerated dose of LKD378, and understand its safety, pharmacokinetics, antitumor activity. The maximum tolerated dose of LDK378 was found to be 750 mg, administered once daily. A response rate of 81% (21/26) was reported in NSCLC patients treated at ≥400 mg whose disease progressed after treatment with Xalkori. Interestingly, responses were seen in patients with brain metastases, suggesting that LDK378 crosses the blood brain barrier. Overall, LDK378 exhibited potent antitumor activity in NSCLC patients with the ALK mutation, including those who have progressed following crizotinib. It looks like a promising new drug to watch out for in phase II and III trials.

Does chemotherapy produce better responses than Tarceva for EGFR wild-type in second-line NSCLC?

The eagerly awaited results of the Italian TAILOR trial were presented in Chicago. While the role of EGFR inhibitors in people whose lung cancer is driven by a mutation in EGFR has been well studied, noticeably less clinical data has been presented from randomized trials in people without a mutation in the EGFR gene. This phase III trial attempted to address that issue.

The results were not altogether surprising, with both median overall survival (OS) and 6-month progression-free survival (PFS) significantly in favor of docetaxel over Tarceva (OS: 3.4 vs 2.4 months, PFS: 28.9% vs 16.9%). In other words, people without a mutation in the EGFR gene respond better to chemotherapy, a finding that reinforces the current treatment approach.

4 Comments

Andy

June 27, 2012

Hi Sally, nice write-ups. I’ve a question for both afatinib and selumetinib: what do you think of their safety profiles, which are also important in determining how useful they’ll be in practice? Thanks!

From what I can recall from the ASCO presentations this year, afatinib has a similar safety profile to EGFR inhibitors such as erlotinib, with the acneiform rash being a class/TKI effect. Other common events included stomatitis/mucositis and paronychia (skin infections around the nails).

Selumetinib and the MEK inhibitors are not the easier partner for combination therapy – they also tend to cause diarrhea (70% of patients experienced it in the trial reported, although none were grade 3/4) as well as nausea and vomiting. Grade 3/4 adverse events included acneiform rash 6.8% (vs none in the docetaxel arm) and asthenia. Hem toxicities were also slightly increased with the combination over docetaxel alone.

Overall from talking to trialists at ASCO, my sense is that the MEK inhibitors will be tougher from a combination standpoint than pan ErbB inhibitors, although neither will be a walk in park.

Elaine

August 26, 2012

Sally, could you kindly expound on comment on erbitux ‘unlikely to see much action in lung ca until a biomarker for it is found’? ECOG trial aside, does this mean that for patients considering tarceva+erbitux or afatinib + erbitux for maintenance NSCLC, these combos may actually just be better (and much cheaper) considered alone?

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